This is the A1 competitive renewal application of a program project that builds on our success in the development of intraoperative photodynamic therapy (PDT) following tumor resection for patients with serosal (peritoneal and pleural) malignancies. This project proposes to identify and study PDT induced local and systemic responses that uniquely interact with the surgical environment to determine local control and long-term outcome. We posit that surgery can both positively and negatively affect the PDT that follows it through its reduction of disease burden and the accompanying induction of pro-inflammatory cytokines and survival signaling that alter the immunologic, molecular and physiologic environment to which PDT will be delivered. We use as our model intraoperative PDT of malignant pleural mesothelioma (MPM) for which we have found unprecedented overall survival and survival time from post-operative recurrence with lung sparing surgery (radical pleurectomy, RP) and pleural PDT (pPDT). It is because of this finding that we have transitioned in this program project to focusing entirely on RP/pPDT for patients with MPM. The overall, long-term goal of this program project is to use RP/pPDT as a model to maximize the potential clinical utility of surgery/PDT as a treatment modality by conducting a two-site randomized clinical trial studying the mechanisms behind the interaction of surgery and PDT and to identify strategies to improve the clinical outcomes with surgery/PDT. The underlying hypotheses are that: 1) pPDT improves RP outcomes by stimulating a) direct cancer cell cytotoxicity, b) changes to the tumor microenvironment, and c) augmentation of antitumor immune responses; 2) surgical resection of tumor induces changes that modify each of these critical facets of pPDT efficacy and 3) modulating these surgically-induced changes will further improve pPDT efficacy. These hypotheses will be addressed in 4 interactive, synergistic projects: Project 1 (Joseph Friedberg) will conduct a prospective randomized Phase II clinical trial looking at RP, with and without intraoperative PDT to the pleura. Project 2 (Steven Albelda), will characterize the impact of PDT on anti-tumor immune responses following surgery and evaluate whether modulating surgically-induced inflammatory signaling can improve PDT efficacy. Project 3 (Keith Cengel) will explore whether baseline or surgically-induced activation of STAT3 and COX-2 signaling pathways represent a significant contributor to local treatment failure in RP/pPDT patients and whether inhibitors targeting these pathways will improve the efficacy of intraoperative PDT. Project 4 (Theresa Busch), will determine the contribution of the vascular microenvironment of MPM in patients receiving intraoperative PDT and to evaluate potential clinical relevance of PDT-induced hemodynamic changes, as well as vascular response contribution to the efficacy of intraoperative PDT. This structure will allow for superior integration and alignment of the clinical analysis aims, including collection of clinical data and samples in Project 1 with the preclinical translational (bench-to-bedside) aims in Projects 2-4.